Supercharching the brain

New drugs promise to improve memory and sharpen mental response. Who should be allowed to take them?

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Sep 16th 2004

DO YOU have an important meeting tomorrow, or perhaps an examination, for which you would like your mental powers to be at their peak? Within a few years, you may have the option of taking a “cognitive enhancer”–a drug that sharpens your mental faculties. During the 1990s–declared “decade of the brain” by America’s Congress and the National Institutes of Health–much progress was made in understanding the processes of memory and cognition. Advances in genetics, molecular biology and brain-imaging technologies allowed researchers to scrutinise the brain’s workings and gave them the potential to create drugs to enhance aspects of its performance. Though there are very few products on the market that reflect this increased understanding, that may soon change.

At least 40 potential cognitive enhancers are currently in clinical development, says Harry Tracy, publisher of NeuroInvestment, an industry newsletter based in Rye, New Hampshire. Some could reach the market within a few years. For millions, these breakthroughs could turn out to be lifesavers or, at the very least, postpone the development of a devastating disease. In America alone, there are currently about 4.5m people suffering from Alzheimer’s disease, and their ranks are expected to grow to 6m by 2020. Mild Cognitive Impairment (MCI), defined as memory loss without any significant functional impairment, is estimated to afflict at least another 4.5m people. Because the majority of MCI patients will eventually develop Alzheimer’s, many doctors believe that intervening in the early stages of the disease could significantly delay its onset.

But there is a fine line between curing the ill and enhancing the well. The gradual deterioration of mental faculties is part of the natural process of ageing. There are now about 85m people aged 50 and over in America, many of whom may already fit the definition of “age-related cognitive decline”, a category so vague it includes people who become distressed over such mild glitches as forgetting their keys or glasses. Should they be offered “cognitive enhancers” too?

And the interest in such drugs will not stop there, predicts James McGaugh, who directs the Centre for the Neurobiology of Learning and Memory at the University of California at Irvine. Next in line could be executives who want to keep the names of customers at the tips of their tongues, or students cramming for exams. “There’s an awful lot of sales potential,” says Dr McGaugh. That is putting it mildly. But are such drugs really feasible–and if they are, who should be allowed to take them?

Thanks for the memories

A handful of small companies are at the forefront of the fledgling field of cognitive enhancement. Among them is six-year-old Memory Pharmaceuticals, based in Montvale, New Jersey, which has two compounds in early-stage clinical trials and recently went public. The company’s visionary and Nobel prize-winning co-founder, Eric Kandel, has been unravelling the processes of learning and memory for more than four decades with the help of Aplysia, a type of colossal sea slug that grows up to a foot in length. While it has only about 20,000 neurons (humans have 100 billion), individual neurons are large enough to be distinguished by eye–making them easy to study.

When a shock is applied to Aplysia’s tail or head, messages travel around a circuit of neurons, causing it to retract its gill for protection. The same fundamental process occurs in humans too: neurons “talk” to each other across a gap, the synapse, via chemicals called neurotransmitters, which bind to receptors at the receiving end. One shock in Aplysia creates a memory that lasts for minutes; several shocks spaced out over time will be remembered for days or longer. Dr Kandel showed that the process of acquiring long-term memories does not change the basic circuitry of nerve cells. Rather, it creates new synaptic connections between them, and solidifies existing ones.

In 1990, Dr Kandel’s laboratory at Columbia University found the first clue to one of the key elements underlying that process–“cyclic AMP response element binding protein”, or CREB. It turns out that CREB functions like a molecular switch that can turn genes off or on, thus manipulating the production of proteins that bring on lasting structural changes between neurons. Lowering the threshold for turning on that switch causes memories to be consolidated more easily. After creating compounds that successfully manipulated the CREB pathway in rodents, the company signed a partnership with Swiss pharmaceutical giant Hoffmann-La Roche worth up to $106m.

Helicon Therapeutics of Farmingdale, New York, is pursuing the same target, with competing patents, albeit more slowly. In the mid-1990s the firm’s co-founder, Tim Tully, a neuroscientist at Cold Spring Harbor Laboratory of Long Island, New York, performed his own groundbreaking CREB studies in fruit flies. In one particular experiment, Dr Tully and his colleagues compared normal flies with those that had been genetically engineered so that the CREB switch was permanently turned on. While crawling in a small tunnel in the presence of an odour, the insects received an electric shock. Just one such jarring experience was enough to teach the enhanced flies to run away from the same odour in future: they had, in effect, perfect recall, or what is sometimes called “photographic memory” in humans. The normal flies, however, required a total of ten training sessions to learn the same lesson. By the end of this year, Helicon hopes to move one particularly promising compound into clinical trials.

You must remember this

Not everyone believes CREB-enhancers will boost human mental performance, however. Among the sceptics is Joe Tsien, director of the Centre for Systems Neurobiology at Boston University, who created a buzz a few years ago when he engineered “Doogie,” a strain of intelligent mice. Dr Tsien points to a study published in the Journal of Neuroscience last year, which found that mice with CREB “deleted” from a part of the brain called the hippocampus showed little impairment of long-term memory formation. Moreover, he notes, CREB is not a brain-specific molecule, but is present throughout the body. “That doesn’t bode well for the notion that it’s a memory switch,” argues Dr Tsien. Even if the drugs work, he adds, nasty side-effects could appear–one of the main reasons promising compounds never make it to the market.

Saegis Pharmaceuticals, based in Half Moon Bay, California, is taking a different approach–three of them, in fact. The company has licensed in three compounds, each one acting on a different pathway in the brain. Moreover, all of them have already demonstrated efficacy in animals, and two of them safety in humans. The company’s lead candidate, SGS742, which has just entered a mid-stage clinical trial for Alzheimer’s disease, appears to alter brain chemistry in several distinct ways. Most importantly, the drug binds to GABA B receptors, which act as pre-synaptic gatekeepers for various neurotransmitters. By docking on to these receptors, SGS742 blocks their inhibitory actions. This enables many more neurotransmitter messengers to travel from one nerve cell to another.

Besides pursuing compounds that originated elsewhere, Saegis is busy developing its own drug pipeline. The firm enlisted Michela Gallagher, a research psychologist at Johns Hopkins University, to help identify new drug targets in animal models. Dr Gallagher, who has studied the ageing brains of rats for more than a decade, has developed an elaborate system with which she grades the rats based on their ability to master a variety of cognitive challenges, such as memorising a specific location in a maze. Interestingly, she has found that both humans and rats develop age-related memory loss gradually and in similar proportion. By comparing the gene-expression profiles of rats of different ages and abilities, she has been able to pinpoint over 300 genes that play a part in the process. Because people share those genes, Dr Gallagher reckons her research will hasten the development of memory drugs.

Currently only a handful of drugs to treat Alzheimer’s are approved in America, and none for MCI. Most of them prevent the breakdown of acetylcholine, a neurotransmitter. Unfortunately, these medications are not that effective. While patients show small gains on tests, many doctors doubt that the scores translate into meaningful lifestyle improvements, such as the ability to continue living at home. Moreover, the drugs often have unpleasant side-effects, such as nausea and vomiting, which may be why they have failed to interest healthy people. But that could change with the next generation of drugs. Because of their huge market potential, any drug approved for MCI will have to show an immaculate safety profile, predicts Dr Tracy.

For an indication of what might happen if a safe and effective cognitive enhancer were to reach the market, consider the example of modafinil. Manufactured by Cephalon, a biotech company based in West Chester, Pennsylvania, and sold under the names “Provigil” and “Alertec”, the drug is a stimulant that vastly improves alertness in patients with narcolepsy, shift-work sleep disorder and sleep apnea. Since it first reached the market in America in 1999, sales have shot through the roof, reaching $290m in 2003 and expected to grow by at least 30% this year.

Much of the sales growth of modafinil has been driven by its off-label use, which accounts for as much as 90% of consumption. With its amazing safety profile–the side-effects generally do not go beyond mild headache or nausea–the drug is increasingly used to alleviate sleepiness resulting from all sorts of causes, including depression, jet lag or simply working long hours with too little sleep. Cephalon itself is now focusing on moving the drug through late-stage clinical trials for attention deficit hyperactivity disorder in children. Ritalin, an amphetamine now widely used to treat this disorder, is in the same category as morphine for its addictive potential. Most experts believe that modafinil, by contrast, is far less likely to be abused.

Nothing new under the sun

While there are those who scoff at the idea of using a brain-boosting drug, Arthur Caplan, a bioethicist at the University of Pennsylvania in Philadelphia, does not think it would be particularly new, or inherently wrong, to do so. “It’s human nature to find things to improve ourselves,” he says. Indeed, for thousands of years, people have chewed, brewed or smoked substances in the hopes of boosting their mental abilities as well as their stamina. Since coffee first became popular in the Arab world during the 16th century, the drink has become a widely and cheaply available cognitive enhancer. The average American coffee drinker sips more than three cups a day (and may also consume caffeine-laced soft drinks).

Prescription drugs, though never intended for widespread use, have followed suit. Ritalin, for example, is used by some college students to increase their ability to study for long hours. Not surprisingly, some worry about the use of such drugs to gain an unfair advantage. Modafinil has already surfaced in doping scandals. Kelli White, an American sprinter who took first place in the 100-metre and 200-metre competitions at last year’s World Championships in Paris, later tested positive for the drug. Initially she insisted that it had been prescribed to treat narcolepsy, but subsequently admitted to using other banned substances as well. As a result, she was forced to return the medals she won last year and, along with a handful of other American athletes, was barred from competitions for two years.

Nonetheless, such performance-enhancing properties are exactly why the armed forces have taken an interest in brain-boosting drugs. For soldiers on the battlefield, who may sleep only four hours a night for weeks, a boost in alertness could mean the difference between life and death. Pilots on long missions are also at risk: fatigue means they have slower reaction times and impaired attention spans, says John Caldwell, a research psychologist at the US Air Force Fatigue Countermeasures Branch, who has been studying the effects of sleep deprivation in pilots for a decade. Worst of all, pilots are prone to “microsleeps”–short, involuntary naps that can last up to 30 seconds. Since the second world war, pilots of American fighter jets have been known to use amphetamines, known as “go pills”, to stop them dozing off at the controls.

But there are drawbacks to amphetamines. Besides their addictive potential, they are strong stimulants, which can prevent soldiers from sleeping when a legitimate opportunity arises. But with modafinil, which has a much more subtle effect on the nervous system, napping is an option, says Dr Caldwell. Last December, America’s air force authorised the use of modafinil as an alternative to dextroamphetamine for two-seater bomber missions lasting more than 12 hours. While the drug has not yet been approved for use by solo fighter pilots, approval is expected soon.

Better than coffee?

Last year, Nancy Jo Wesensten, a research psychologist at the Walter Reed Army Institute of Research in Silver Spring, Maryland, compared the effects of three popular alertness drugs–modafinil, dextroamphetamine and caffeine–head to head, using equally potent doses. Forty-eight subjects received one of the drugs, or a placebo, after being awake for 65 hours. The researchers then administered a battery of tests. All of the drugs did a good job restoring wakefulness for six to eight hours. After that, says Dr Wesensten, the performance of the subjects on caffeine declined because of its short half-life (a fact that could be easily remedied by consuming another dose, she points out). The other two groups reached their operational limit after 20 hours–staying awake for a total of 85 hours.

When the researchers looked at the drugs’ effects on higher cognitive functions, such as planning and decision-making, they found each drug showed strengths and weaknesses in different areas. Caffeine was particularly effective in boosting a person’s ability to estimate unknown quantities. When asked 20 questions that required a specific numeric answer–such as “how high off a trampoline can a person jump?”–92% of volunteers on caffeine and 75% on modafinil showed good estimation skills. But only 42% on dextroamphetamine did so–the same proportion as the sleep-deprived subjects who had received a placebo.

The Defence Advanced Research Projects Agency (DARPA), the research arm of America’s defence department, is funding an initiative to find new and better ways to sustain performance during sleep deprivation. Among its collaborators are Yaakov Stern, a neuroscientist, and Sarah Lisanby, a psychiatrist, both of Columbia University. Using functional magnetic-resonance imaging, Dr Stern has been observing the brains of healthy volunteers before and after forgoing sleep.

In the process, he has discovered a neural circuit that is linked to prolonged periods of wakefulness while performing memory tasks. Interestingly, its areas of activation vary from person to person, depending on the ability to tolerate sleep deprivation. Dr Lisanby is an expert in transcranial magnetic stimulation, the use of strong magnetic fields to facilitate or impede the communication of nerve cells using a coil held close to the head. She now plans to test stimulating the very regions in the brain that appear to correspond to better cognitive performance during long hours of wakefulness.

DARPA is also supporting the research of Samuel Deadwyler, a neuroscientist at Wake Forest University in Winston-Salem, North Carolina, who is studying the effects of ampakines, so called because they bind to AMPA receptors. There, they amplify the actions of glutamate, a neurotransmitter involved in two-thirds of all brain communications. Roger Stoll, the boss of Cortex Pharmaceuticals, which has been developing the compounds, has called them “a hearing aid for the brain”.

According to Dr Deadwyler’s tests in primates, Cortex’s new drug candidate, CX717, which just entered human clinical trials, appears to eliminate the cognitive deficits that go hand in hand with sleep loss. Monkeys deprived of sleep for 30 hours and then given an injection of the compound even do slightly better in short-term memory tests than well-rested monkeys without the drug. And unlike amphetamines, which put the whole body in a state of alert, CX717 only increases activity in key brain areas–without any addictive potential.

What pills cannot do

Drugs that can boost wakefulness or provide a short-term improvement in mental agility exist today, and seem likely to proliferate in future. But since coffee does both already–caffeine is humanity’s most widely consumed drug–there is little reason to object to this state of affairs, provided no laws are broken and the risks of side-effects or addiction are minimal.

Besides, cognitive enhancers merely improve the working of the brain: they cannot help people remember something they never learned in the first place. No single pill will make you a genius, says Fred Gage, a neuroscientist at the Salk Institute in California, as there is no pharmaceutical substitute for a rich learning environment. In experiments with genetically identical mice, he found that the ones brought up with lots of toys and space had 15% more neurons in an area of the brain important for memory formation. And the brain had not just created more cells: fewer of them were dying off. “Any pill coming down the road”, says Dr Gage, “is going to be taken in the context of how you behave.”

And too much enhancement might even be counter-productive–at least for healthy people. As Dr Kandel and his colleague Larry Squire, of the University of California, San Diego, point out in their book “Memory: From Mind to Molecules”, there is a reason why the brain forgets things: to prevent cluttering up our minds. People with the natural ability to remember all sorts of minute details often get bogged down in them, and are unable to grasp the larger concepts. So it remains to be seen whether a pill can be any more effective than a good night’s sleep and a strong cup of coffee.